The anticoagulant, warfarin, has been used since the 1950s to slow blood clotting, including for the prevention and treatment of deep vein thrombosis. Additionally, it has been employed in the prevention of thromboembolism in patients with atrial fibrillation or heart valve(s) replacement. Warfarin remains one of the most commonly used anticoagulants worldwide.

The most common side effect of warfarin is bleeding; regular international normalised ratio (INR) monitoring helps to ensure that the desired balance is achieved between over-and-under anticoagulation to minimise the risk of unwanted bleeds. In comparison to newer agents, such as dabigatran and rivaroxaban, the rates of intracranial bleeding are slightly higher for warfarin, the greatest risk of bleeding being within the first three months of commencing therapy. The risk factors associated with an increased risk of bleeding include drug interactions, INR>4, length of therapy, and patient factors such as age, comorbidities and the risk of falls. Modifying any risk factors identified, and educating patients on how to reduce their risk of bleeds, can help improve compliance and reduce anxiety surrounding warfarin therapy.

Vitamin K1 is used as an antidote to reverse over-warfarinisation. Vitamin K1, given intravenously, has a fast and predictable onset of action and is preferred over the oral route of administration. Vitamin K1, or phytomenadione, is available in 10mg/mL ampoules under the trade names Konakion® MM (1mL) or Konakion® MM Paediatric (0.2mL).

Depending on the degree of over-warfarinisation, either Prothrombinex-VF® (PTX-VF) or fresh frozen plasma (FFP) may be used to replace depleted levels of clotting factors. PTX-VF is a prothrombin complex used to replace factors II, IX and X, while FFP supplements depleted levels of factors II, VII, IX and X. FFP is a blood product requiring transfusion, whilst PTX-VF is a freeze-dried concentrate that can be simply reconstituted prior to administration. Some other advantages of using PTX-VF over FFP are:

  • It acts quickly (within 15 minutes)
  • It doesn’t require special facilities for storage
  • Transfusion-related reactions can be avoided
  • It can be rapidly reconstituted without the need for thawing, and
  • The patient’s blood group doesn’t need to be checked before administration.

PTX-VF, however, contains small amounts of heparin and is therefore contraindicated in patients with a history of heparin-induced thrombocytopenia. PTX-VF is also contraindicated in patients with active clots.

At present there are a number of slightly differing guidelines for the management of bleeding associated with over-warfarinisation, but no studies have been conducted to compare them. The Australian Medicines Handbook (AMH) recommends that local protocols be followed.

The Australasian Society of Thrombosis and Haemostasis updated their guidelines for the management of warfarin bleeds in 2013, which was based on current evidence and clinical experience. These guidelines distinguish between clinically significant but non-life-threatening bleeding and life-threatening bleeding; hence a few differences exist in their approach to the management of over-warfarinisation.

Table 1. Management of over-warfarinisation in patients with bleeding.

Clinical Setting Recommendations
INR ≥ 1.5 with

  • critical organ bleeding (life threatening)
  • or
  • intracranial bleeding
 Cease warfarin and administer:

  • Vitamin K1 IV 5–10mg and
  • PTX-VF IV 50IU/kg and FFP 150–300mL
  • or
  • FFP can be administered at 15mL/kg if PTX-VF is unavailable
INR ≥ 2.0 with

  • clinically significant bleeding (but not life threatening)
 Cease warfarin and administer:

  • Vitamin K1 IV 5–10mg and
  • PTX-VF IV 35–50IU/kg, according to INR
  • or
  • FFP can be administered at 15mL/kg if PTX-VF is unavailable
Any INR with minor bleeding
  • Omit warfarin dose
  • Repeat INR the following day and adjust the warfarin dose to maintain target range
  • Consider vitamin K1 1–2mg orally or 0.5–1mg IV if bleeding risk is high:
    • (bleed in the past 4 weeks),
    • major surgery within the past 2 weeks,
    • known liver disease,
    • concomitant antiplatelet therapy,
    • thrombocytopenia
    • INR > 4.5

It is important that any over-the-counter and complementary medicines that the patient was taking prior to admission into hospital are not omitted from the medical history, as they may affect the INR of a patient on warfarin.

To minimise the risk of bleeding associated with warfarin therapy all patients should be counselled on the importance of:

  1. Informing all health professionals, including dentists and physiotherapists, that they are taking warfarin
  2. Always checking with a pharmacist or doctor before starting or stopping any medicines, including over the counter items and complementary medicines
  3. Checking with the doctor before commencing any sporting activities that carry a high risk of injury
  4. Notifying the doctor if they feel ill
  5. Maintaining a healthy, well-balanced, diet that doesn’t vary too much.

References:

  1. Borosak M, Choo S, Street A. Warfarin: balancing the benefits and harms. Aust Prescr 2004; 27:88-92.
  2. Chalmers L. Peterson G, Bereznicki L. Warfarin: Important information for patients. 47th ed. St Leonards: Aspen Pharma Pty Ltd; 2012.
  3. Kruger PC, Le Viellez AS, Herrmann RP. Prothrombinex-VF use in warfarin reversal and other indications. Med J Aust 2012; 196(7):462‐5.
  4. National Prescribing Service. How to manage warfarin bleeds — updated recommendations. NPS Direct 2013. April 18.
  5. NPS MedicineWise [Internet].Canberra: National Prescribing Service; Comparing dabigatran and warfarin for preventing stroke. 2013 Jun 21.
  6. Prothrombinex-VF (human prothrombin complex) Australian approved product information. Broadmeadows: CSL Limited. Approved 17 June 2011.
  7. Rossi S (editor). Australian Medicines Handbook 2013. Adelaide: Australian Medicines Handbook Pty Ltd; 2013.
  8. Tran HA, Chunilal SD, Harper PL, Tran H, Wood EM, Gallus AS; Australasian Society of Thrombosis and Haemostasis. An update of consensus guidelines for warfarin reversal. Med J Aust 2013; 198(4):198‐199.
  9. van der Meer FJ, Rosendaal FR, Vandenbroucke JP, Briët E. Bleeding complications in oral anticoagulant therapy. An analysis of risk factors. Arch Intern Med 1993; 153(13):1557-62.
  10. WA Medication Safety Group Anticoagulant Working Group. Living with warfarin. Information for patients. Perth: WA Department of Health; 2013.

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